In general, analgesics fall into two broad categories. The simple analgesics, such as aspirin, are most effective against pain of integumental origin, headache, and muscle ache; the narcotics are more useful for deep or visceral pain. Narcotic analgesics such as morphine produce more profound effects than simple analgesics, and are potentially addicting, with the development of tolerance and physical dependence. The morphine-like analgesics appear to work through interaction with the endorphin/enkephalin system of the central nervous system; many, if not all of the simple, non-narcotic analgesics appear to work by inhibition of prostaglandin synthetase. The effect of narcotics is to elevate the pain threshold above the normal level; the non-narcotic analgesics act to raise an abnormally low pain threshold to the normal level. The narcotic analgesics are antagonized by compounds such as naloxone; the non-narcotic analgesics are not.
Capsaicin (8-methyl-N-vanillyl-6-nonenamide), which is the pungent component of paprika, is a potent analgesic. However, it appears to be largely unrelated to the two known classes of analgesics. In certain tests, it produces a level of analgesia comparable to morphine, yet it is not antagonized by classical narcotic antagonists, such as naloxone. It effectively prevents the development of cutaneous hyperalgesia, but appears to have minimal effects on normal pain responses at moderate doses. At high doses capsaicin also exerts analgesic activity in classical models of deep pain, elevating the pain threshold above the normal value.
Capsaicin has the following structure: ##STR1## where R is --(CH.sub.2).sub.4 CH.dbd.CH--CH(CH.sub.3).sub.2
Capsaicin can be readily obtained by the ethanol extraction of the fruit of capsicum frutescens or capsicum annum. It is available commercially from a variety of suppliers, and can also be prepared synthetically by published methods. In some commercially available forms of capsaicin, R=--(CH.sub.2).sub.7 C.sub.3. This "pseudocapsaicin" is pharmacologically indistinguishable from natural capsaicin. The present invention encompasses the use of both forms, and where the term "capsaicin" is used, both forms are meant.
Nonsteroidal anti-inflammatory drugs (NSAIDS) generally have a low pH and can be corrosive to portions of the gastrointestinal tract, especially the stomach lining. Recent research has shown that these drugs, when taken orally, can increase the patients' risk for developing peptic ulcer disease and upper gastrointestinal bleeding, especially in elderly persons. The detrimental effects of these drugs on the gastrointestinal tract increase as the dose of the NSAID increases. Therefore, there is a need for a method of delivering these drugs to the body that can bypass the gastrointestinal tract and provide effective relief at lower doses.
The main reason why relatively large doses of NSAIDS must be used when the drugs are taken orally is that the drugs are very effectively metabolized in the liver before they can be delivered to the circulation system of the patient, (i.e., the so-called "first pass" metabolism). For example, first pass metabolism can decrease the amount of drug that reaches the site of action by about 30 to 70 percent depending on the chemical make-up of the drug. Since the efficacy of pharmaceutical products in general depends not only on the amount of the active ingredient that enters the circulatory system but also on the amount of active ingredient that reaches the receptor site or site of action, it should be apparent that any method of providing the active ingredient to the body which bypasses the liver and/or stomach would be very desirable and could also result in more rapid and predictable effects with a given dosage. Accordingly, an effective transdermal delivery system for NSAIDS would be very desirable, especially for treating pain and discomfort associated with the muscles or joints of a mammal.
Pamabrom is an 8-Bromotheophylline compound with 2-amino-2-methyl-1-propanol (1:1) which is used as a diuretic agent. The chemical structure of pamabrom is set forth below. ##STR2##
The term nonsteroidal anti-inflammatory drugs (NSAIDS), as used herein, includes, but is not necessarily limited to, the following substances: diflunisal; fenoprofen; ibuprofen; indomethacin; meclofenamate; naproxen; oxyphenbutazone; phenylbutazone; piroxicam; sulindac; tolmetin; salicylates and zomepirac.
The term "pharmaceutically-acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent involved in carrying or transporting a chemical agent from one organ or portion of the body to another organ or portion of the body.
The term "transdermal delivery" as used herein means administration of the pharmaceutical composition topically to the skin wherein the active ingredient will be percutaneously delivered in a therapeutically effective amount.
The term "transdermal patch" as used herein means a skin patch to be applied to the mammals skin containing the pharmaceutical composition. The technology for constructing transdermal patches is well known in the pharmaceutical art.
The terms "backing layer" and "reservoir" as used herein are components of the transdermal patch. Suitable materials and designs are well known in the transdermal drug delivery art. See for example D. Hsien, "Multiple Lamination for Transdermal Patches," Controlled Release Systems Fabrication Technology, Vol. 1, pp. 167-188. 1988.
Eucalyptol is a well-known chemical compound which has long been used as an inhalational expectorant. It is also known by the names cineole and cajeputol. The art is also well-versed in the preparation of eucalyptol.
Menthol is a secondary alcohol obtained naturally from peppermint or other mint oils or prepared synthetically. Menthol has many uses as an ingredient in various medicinal preparations due to its analgesic, local anesthetic and counter irritant properties. It is known in the pharmaceutical art that menthol acts to enhance the percutaneous transfer of systemically active drugs in mammals.